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Yellow fever vaccine.

Yellow fever, a mosquito-borne viral hemorrhagic fever, is one of the most lethal diseases of humankind. The etiologic agent is the prototype member of the genus Flavivirus, family Flaviviridae, a group of small, enveloped, positive-sense, single-strand RNA viruses. Approximately one in seven people who become infected develop a rapidly progressive illness, with hepatitis, renal failure, hemorrhage and cardiovascular shock, with a case fatality rate of 20-50%. Yellow fever occurs in sub-Saharan Africa and tropical South America, where it remains a continuing public health problem of varying magnitude, depending on the level of vaccination coverage in the human population and cyclical, ecologic and climatic factors that influence virus transmission.

Animals↗

Current status of the Arilvax; yellow fever vaccine.

Yellow fever is a viral hemorrhagic fever that involves dysfunction of the liver and kidneys. There is no antiviral therapy available and vaccination is a major strategy in the control of this important public health problem. Yellow fever vaccine is a live attenuated vaccine, strain 17D, which is very safe and efficacious and induces long-term protective immunity in vaccinees. The vaccine is produced by six manufacturers worldwide, including Arilvax by Chiron vaccines (CA, USA) that is marketed in at least ten countries. Acambis (MA, USA) have acquired the rights to sell and market Arilvax in the USA, and have undertaken three clinical trials to obtain data for a Biological License Application that should proceed in 2005.

Clinical Trials, Phase III as Topic↗

[Yellow fever epidemic in the extreme North of Cameroon in 1990: first yellow fever virus isolation in Cameroon].

Some two years ago, suspicious cases of yellow fever (YF) were reported in northern Cameroon. A deadly epidemic broke out during the second half of the rainy season (from 15 September to 22 December 1990) with 180 known cases, of which 125 died. The real figures could have been between 5000 and 20,000 cases with between 500 and 1000 deaths. The affected area was within the yellow fever belt, which is situated around latitude 11 degrees North and 14 degrees East. In this mountainous area (altitude, about 800 m) the rural inhabitants are scattered, with a high density of 200,000 people per 1000 km2. Investigations began at the start of the dry season and a strain of yellow fever virus was isolated for the first time in Cameroon. A study of 107 serum samples (23 families in 11 villages) was carried out by immunofluorescence and ELISA, which showed 20% IgM carriers for yellow fever virus and nothing for the three other flaviviruses, although these were largely present; there were up to 98% crossed reactions in IgG with dengue 2 and West Nile strains. The under-10 age group represented 63% of the IgM carriers. An entomological study was carried out at the same time. It permitted the capture of Aedes aegypti, A. furcifer, A. luteocephalus and the identification of numerous potential larval sites, at times still in the productive phase of A. aegypti which is considered to be the principal vector.(ABSTRACT TRUNCATED AT 250 WORDS)

Aedes↗

Genetic relationships and evolution of genotypes of yellow fever virus and other members of the yellow fever virus group within the Flavivirus genus based on the 3' noncoding region.

Genetic relationships among flaviviruses within the yellow fever (YF) virus genetic group were investigated by comparing nucleotide sequences of the 3' noncoding region (3'NCR). Size heterogeneity was observed between members and even among strains of the same viral species. Size variation between YF strains was due to duplications and/or deletions of repeated nucleotide sequence elements (RYF). West African genotypes had three copies of the RYF (RYF1, RYF2, and RYF3); the Angola and the East and Central African genotypes had two copies (RYF1 and RYF3); and South American genotypes had only a single copy (RYF3). Nucleotide sequence analyses suggest a deletion within the 3'NCR of South American genotypes, including RYF1 and RYF2. Based on studies with the French neurotropic vaccine strain, passage of a YF virus strain in cell culture can result in deletion of RYF1 and RYF2. Taken together, these observations suggest that South American genotypes of YF virus evolved from West African genotypes and that the South American genotypes lost RYF1 and RYF2, possibly in a single event. Repeated sequence elements were found within the 3'NCR of other members of the YF virus genetic group, suggesting that it is probably characteristic for members of the YF virus genetic group. A core sequence of 15 nucleotides, containing two stem-loops, was found within the 3'NCR of all members of the YF genetic group and may represent the progenitor repeat sequence. Secondary structure predictions of the 3'NCR showed very similar structures for viruses that were closely related phylogenetically.

Africa, Western↗

Risk of fatal adverse events associated with 17DD yellow fever vaccine.

Yellow fever (YF), an acute infectious disease, is endemic in the north and central-west of Brazil. This disease can be prevented by the use of a vaccine. In Brazil, four fatal adverse events have been associated with the YF vaccine used in the country (17DD vaccine). We briefly describe the last two fatalities, and estimate the risk of 17DD-associated fatal adverse events under different epidemiological scenarios. Controversies regarding the appropriate denominator that enters the estimation of risk serve as a motivation for each proposed scenario. The statistical procedures used show optimum behaviour when assessing the risk of rare events. Risk estimates vary from 0.043 (95 % CI 0.017-0.110) to 2.131 (95 % CI 0.109-12.071) fatalities per million doses administered. The robust estimates of the risk of fatal adverse events we present constitute an important element in future risk-benefit analysis and point to the need for good quality vaccine coverage and adverse-events surveillance data to assess the risk of vaccination. Although vaccination of YF endemic regions is necessary to maintain low disease prevalence, preventive administration of YF vaccine to the entire population should be cautiously analysed.

Adult↗

Genome analysis and phylogenetic relationships between east, central and west African isolates of Yellow fever virus.

Yellow fever virus (YFV), a reemerging disease agent in Africa and South America, is the prototype member of the genus Flavivirus. Based on examination of the prM/M, E and 3' non-coding regions of the YFV genome, previous studies have identified seven genotypes of YFV, including the Angolan, east/central African and east African genotypes, which are highly divergent from the prototype strain Asibi. In this study, full genome analysis was used to expand upon these genetic relationships as well as on the very limited full genome database for YFV. This study was the first to investigate genomic sequences of YFV strains from east and central Africa (Angola71, Uganda48a and Ethiopia61b). All three viruses had genomes of 10 823 nt in length. Compared with the prototype strain Asibi (from west Africa) they were approximately 25 % divergent in nucleotide sequence and 7 % divergent in amino acid sequence. Comparison of multiple flaviviruses in the N-terminal region of NS4B showed that amino acid sequences were variable and that west African strains of YFV had an amino acid deletion at residue 21. Additionally, N-linked glycosylation sites were conserved between viral genotypes, while codon usage varied between strains.

Africa, Central↗

Stability-related studies on 17D yellow fever vaccine.

Yellow fever (YF) vaccine using the 17D strain of YF attenuated virus has been produced at the Institut Pasteur in Dakar since 1962. Until now, the stabilised YF had an expiry date of utilization of two years from the end of the lot control process under storage at +4 degrees C. We conducted a stability study to assess the three full year validity of this preparation, when correctly stored at +4 degrees C to optimise the conditions of production, storage and availability of such a vaccine. The activity of 19 consecutive batches of vaccines kept for three years at +4 degrees C was compared to that of the same batches that were kept three years at -20 degrees C. Using the in vitro microculture method, we found that three-year storage at +4 degrees C induced a higher loss of activity than storage at -20 degrees C or than the accelerated degradation test of vaccines kept for 14 days at 37 degrees C. Whatever the conditions of storage, in all cases decreases in activity were below the WHO's requirements, i.e., < 1 log PFU/dose, and residual activity of the selected batches was over 1000 mouse LD50 per dose. We demonstrated that the 17D YF vaccine produced in Dakar has a shelf-life of three years and that its required potency was maintained at +4 degrees C, after reconstitution with saline diluent, following three-year storage at +4 degrees C.

Animals↗

[Serologic survey for yellow fever and other arboviruses among inhabitants of Rio Branco, Brazil, before and three months after receiving the yellow fever 17D vaccine].

During a yellow fever vaccination campaign among residents of Rio Branco (Acre State), the frequency of HI antibodies to the most prevalent arboviruses in the Amazon region and to yellow fever virus was determined before and three months after immunization with YF 17D vaccine. From 390 inhabitants included in the first phase of serologic survey (August 1999), only 190 provided a second serum sample, after the use of 17D vaccine (January 2000). Among first phase samples, the frequency of HI antibodies was: 17D (27.2%); Ilheus (5.9%); Mayaro (5.4%); Caraparu (4.9%); Dengue-2 (4.1%); Oropouche (2.3%); and Dengue-1 (0.3%). In the second study phase, the serologic conversion to YF reached 89.7% among previously negative persons. Serologic conversions were also observed to Ilheus (6.2%); Dengue-3 (3.2%); Mayaro (1.1%); and Oropouche (1.1%) viruses. In conclusion, considering the high YF antibody rate after vaccination, the risk of urban yellow fever seems insignificant, although the lower prevalence of HI antibodies to dengue viruses, is of concern and inhabitants are under high risk of dengue outbreaks, especially to DEN-3 recently introduced in Brazil, as was observed in 2000 and 2001 with DEN-1 and DEN-2.

Antibodies, Viral↗

Isolation and characterization of wild type yellow fever virus in cases temporally associated with 17DD vaccination during an outbreak of yellow fever in Brazil.

A mass vaccination was carried out in the state of Minas Gerais, Southeast region of Brazil, to control an outbreak of sylvatic yellow fever in 2001. During the outbreak the surveillance system identified two fatal cases temporally associated with YF vaccination. Virus recovered from blood and postmortem samples of both cases was identified as yellow fever virus. Partial nucleotide sequence of parts of prM/E and the non-structural (NS) 5 genes and 3' non-coding region (3' NCR) was employed to characterize the origin of yellow fever virus (YFV) involved in both cases. Wild-type YFV was identified as the etiologic agent responsible for the disease.

Adult↗

Protection of mice against yellow fever virus encephalitis by immunization with a vaccinia virus recombinant encoding the yellow fever virus non-structural proteins, NS1, NS2a and NS2b.

Recent evidence of a protective immune response to the flavivirus non-structural protein, NS1, has suggested its incorporation into possible recombinant vaccines. The region of the 17D yellow fever virus (YFV) genome encoding the C terminus of envelope glycoprotein and extending to the N terminus of non-structural protein NS3 (NS1-NS2a-NS2b; nucleotides 2030 to 4940) was expressed in vaccinia virus and physical and immunogenic properties of the NS1 moiety were studied. Recombinant NS1 protein, and native YFV NS1, was detected at the surface of infected cells by immunofluorescence and by immune cytolysis after treatment with anti-NS1 antibody and complement. NS1 was also detected in the extracellular medium as a secreted form. Recombinant NS1 was immunoprecipitated as a single protein of approximately the same size as native 17D YFV NS1. Unboiled, both recombinant and native NS1 formed polymers of high Mr. Immunization of mice with this recombinant vaccinia virus stimulated production of non-neutralizing, complement-fixing cytolytic antibody and conferred partial protection against lethal intracerebral inoculation of mice with live 17D YFV.

Animals↗

Comparison of the nucleotide and deduced amino acid sequences of the structural protein genes of the yellow fever 17DD vaccine strain from Senegal with those of other yellow fever vaccine viruses.

The nucleic acid and deduced amino acid sequences of the structural proteins of the 17DD vaccine strain of yellow fever (YF) virus originating from Senegal are compared with those published for other vaccine strains of YF virus. Even though the 17D-204 and 17DD substrains of 17D diverged at passage 195 of 17D, they show a very high degree of nucleotide (99.5%) and amino acid (99.5%) homology over this region. The sequences are discussed with respect to monoclonal antibodies that can distinguish between 17DD and 17D-204 substrains of YF vaccines.

Amino Acid Sequence↗

Yellow fever: an update.

Yellow fever, the original viral haemorrhagic fever, was one of the most feared lethal diseases before the development of an effective vaccine. Today the disease still affects as many as 200,000 persons annually in tropical regions of Africa and South America, and poses a significant hazard to unvaccinated travellers to these areas. Yellow fever is transmitted in a cycle involving monkeys and mosquitoes, but human beings can also serve as the viraemic host for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean and Asia. Here I review the clinical features of the disease, its pathogenesis and pathophysiology. The disease mechanisms are poorly understood and have not been the subject of modern clinical research. Since there is no specific treatment, and management of patients with the disease is extremely problematic, the emphasis is on preventative vaccination. As a zoonosis, yellow fever cannot be eradicated, but reduction of the human disease burden is achievable through routine childhood vaccination in endemic countries, with a low cost for the benefits obtained. The biological characteristics, safety, and efficacy of live attenuated, yellow fever 17D vaccine are reviewed. New applications of yellow fever 17D virus as a vector for foreign genes hold considerable promise as a means of developing new vaccines against other viruses, and possibly against cancers.

Aedes↗

[The risk of yellow fever in travellers].

Yellow fever is a tropical virus disease characterised by high fever, jaundice, heart and kidney failure, and haemorrhagic diathesis. The causative Flavivirus is endemic in parts of tropical Africa and South America and is transmitted among humans and primates by mosquitoes. The chance that an unvaccinated traveller to West Africa will die of yellow fever is estimated at 1:650 to 1:5000 visitors per month of stay, depending on whether an epidemic occurs. Vaccination with the attenuated yellow fever Asibi 17D virus results in limited virus replication in the body and long-term protection due to the formation of neutralising antibodies. Vaccination is contraindicated in immunocompromised persons. Serious disseminated disease and encephalitis due to infection with the vaccine virus strain are seen more often in the elderly. One should therefore refrain from vaccination in persons over 60 years of age when the risk of infection is negligible. In recent years, the number of yellow fever epidemics has risen substantially, particularly in West Africa and the Amazon region. Reintroduction of yellow fever vaccination in childhood vaccination programmes is necessary in endemic areas to turn the tide of increasing outbreaks of yellow fever.

Animals↗